POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY

Original Issue Date (Created): 12/8/2003 Most Recent Review Date (Revised): 3/29/2016 Effective Date: 1/1/2017 POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY I. POLICY Opioid antagonists under heavy sedation or anesthesia is considered investigational as a technique for opioid detoxification (i.e., ultra-rapid detoxification), as there is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this procedure. Cross-reference: MP-2.301 Treatment of Opiate and Alcohol Addiction II. PRODUCT VARIATIONS TOP This policy is applicable to all programs and products administered by Capital BlueCross unless otherwise indicated below. BlueJourney HMO* BlueJourney PPO* *Refer to the following: Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) 130.6, Treatment of Drug Abuse (Chemical Dependency); and Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) 130.7, Withdrawal Treatments for Narcotic Addictions. Page 1

III. DESCRIPTION/BACKGROUND TOP The use of relatively high doses of opioid antagonists under deep sedation or general anesthesia is a technique for opioid detoxification and is known as ultra-rapid detoxification. It is a potential alternative to standard detoxification that allows patients to avoid the acute symptoms associated with initial detoxification. Ultra-rapid detoxification is used in conjunction with maintenance treatments (e.g., oral opioid antagonists and psychosocial support. The traditional treatment of opioid addiction involves substituting the opiate (i.e., heroin) with an equivalent dose of a longer acting opioid antagonist, i.e., methadone, followed by tapering to a maintenance dose. Methadone maintenance therapy does not resolve opioid addiction, but has been shown to result in improved general health, retention of patients in treatment, and a decrease in the risk of transmitting HIV or hepatitis. However, critics of methadone maintenance point out that this strategy substitutes one drug of dependence for the indefinite use of another. Detoxification followed by abstinence is another treatment option, which can be used as the initial treatment of opioid addiction, or offered as a final treatment strategy for patients on methadone maintenance. Detoxification is associated with acute symptoms followed by a longer period of protracted symptoms (i.e., 6 months) of withdrawal. Although typically not life threatening, acute detoxification symptoms include irritability, anxiety, apprehension, muscular and abdominal pains, chills, nausea, diarrhea, yawning, lacrimation, sweating, sneezing, rhinorrhea, general weakness, and insomnia. Protracted withdrawal symptoms include a general feeling of reduced well-being and drug craving. Relapse is common during this period. Detoxification may be initiated with tapering doses of methadone or buprenorphine (an opioid agonist-antagonist), treatment with a combination of buprenorphine and naloxone (an opioid antagonist), or discontinuation of opioids and administration of oral clonidine and other medications to relieve acute symptoms. However, no matter what type of patient support and oral medications are offered, detoxification is associated with patient discomfort, and many patients may be unwilling to attempt detoxification. In addition, detoxification is only the first stage of treatment. Without ongoing medication and psychosocial support after detoxification, the probability is low that any detoxification procedure alone will result in lasting abstinence. Opioid antagonists, such as naltrexone, may also be used as maintenance therapy to reduce drug craving and thus reduce the risk of relapse. Dissatisfaction with current approaches to detoxification has led to interest in using relatively high doses of opioid antagonists, such as naltrexone, naloxene, or nalmefene under deep sedation with benzodiazepine or general anesthesia. This strategy has been referred to as "ultra-rapid," "anesthesia assisted," or "one-day" detoxification. The use of opioid antagonists accelerates the acute phase of detoxification, which can be completed within 24 48 hours. Since the patient is under anesthesia, the patient has no discomfort or memory of the symptoms of acute withdrawal. Various other drugs are also administered to control acute withdrawal symptoms, such as clonidine (to attenuate sympathetic and hemodynamic effects of withdrawal), ondansetron (to control nausea and vomiting), and somatostatin (to control diarrhea). Hospital admission is Page 2

required if general anesthesia is used. If heavy sedation is used, the program can potentially be offered on an outpatient basis. Initial detoxification is then followed by ongoing support for the protracted symptoms of withdrawal. In addition, naltrexone may be continued to discourage relapse. Ultra-rapid detoxification may be offered by specialized facilities. Neuraad Treatment Centers, Nutmeg Intensive Rehabilitation, and Center for Research and Treatment of Addiction (CITA) are examples. These programs typically consist of 3 phases: a comprehensive evaluation, inpatient detoxification under anesthesia, and finally, mandatory post-detoxification care and follow-up. The program may be offered to patients addicted to opioid or narcotic drugs such as opium, heroin, methadone, morphine, demerol, dilaudid, fentanyl, oxycodone, hydrocodone, or butorphanol. Once acute detoxification is complete, the opioid antagonist naltrexone is often continued to decrease drug craving, with the hope of reducing the incidence of relapse. Regulatory Status In October 2002, the buprenorphine monotherapy product, Subutex, and a buprenorphine/naloxone combination product, Suboxone (both Reckitt Benckiser) received was approved under a new drug application by the U.S. Food and Drug Administration for use in opioid addiction treatment. IV. RATIONALE TOP This assessment of ultrarapid opioid detoxification, focuses on data reporting the severity and duration of withdrawal symptoms and the short- and long-term outcomes of maintenance of abstinence in distinct populations of patients, based on type and duration of addiction. Efficacy outcomes will be balanced against the safety considerations of deep sedation or general anesthesia in conjunction with naloxone. In 2010, Gowing et al published a Cochrane review on opioid antagonists under heavy sedation or anesthesia for opioid withdrawal. 1 A total of 9 studies including 1109 participants were eligible for inclusion; there were 8 randomized controlled trials (RCTs) and 1 non-rct. Four studies compared the intervention to conventional approaches of withdrawal, and 5 compared different regimens of antagonist-induced withdrawal. In 5 of the studies, all participants were withdrawing from heroin or other short-acting opioids; in 3 studies, they were using heroin and/or methadone and, in 1 study, all participants were withdrawing from methadone. Due to differences in study designs (eg, antagonist and anesthesia or sedation regimens, comparison interventions, outcome variables), few pooled analyses could be conducted. Findings from 3 trials (total N=240) comparing antagonist-induced and conventional withdrawal were pooled for several outcome variables. The number of participants completing maintenance treatment was significantly higher in the antagonist-induced group than in the conventional treatment group (relative risk [RR], 4.28; 95% confidence interval [CI], 2.91 to 6.30). The Page 3

number of participants who continued maintenance treatment or were abstinent at 12 months also favored the antagonist-induced group (RR=2.77; 95% CI, 1.37 to 5.61). Safety data from these 3 studies were not pooled. One of the studies reported no adverse events (AEs), and 1 only reported AEs in patients who received octreotide (a somatostatin analog) during the anesthetic procedure; 7 of these 11 patients (64%) experienced vomiting and/or diarrhea. The third study reported 3 serious AEs, all of which occurred in the anesthesia group. There were no pooled analyses of the results of studies that evaluated the efficacy of differing opioid antagonist withdrawal regimens. One meta-analysis of safety data from 2 studies (total N=572) found a statistically significantly higher rate of AEs with heavy sedation compared with light sedation (RR=3.21; 95% CI, 1.13 to 9.12). Other AEs included high rates of vomiting in several studies and, in 1 study, episodes of irregularities in respiratory patterns during withdrawal. The authors of the Cochrane review commented that, due to variability among the trials, it is not possible to identify standard treatment regimens for antagonist-induced withdrawal in conjunction with heavy sedation or anesthesia. They concluded that the increased risk of clinically significant adverse events associated with withdrawal under heavy sedation or anesthesia make the value of anesthesia-assisted antagonist-induced withdrawal questionable. A representative RCT included in the Cochrane review was a 2005 trial by Collins et al. 2 In this study, 106 persons addicted to heroin were randomly assigned to undergo detoxification with an anesthesia-assisted rapid opioid detoxification, buprenorphine-assisted rapid opioid detoxification, or clonidine-assisted opioid detoxification. All study participants received an additional 12 weeks of outpatient naltrexone maintenance. Mean withdrawal severities were similar among the 3 groups, and treatment retention in the 12-week follow-up period was also similar. However, the anesthesia procedure was associated with 3 potentially significant lifethreatening AEs. The authors concluded that the data did not support the use of general anesthesia for heroin detoxification. Among the AEs reported in the Cochrane review, vomiting under sedation is particularly worrisome due to the threat of aspiration. Techniques reported to minimize this risk include intubation, use of prophylactic antibiotics, and the use of medication to diminish the volume of gastric secretions. Several deaths occurring either during anesthesia or immediately thereafter have been reported. 3-6 Also, deaths subsequent to ultrarapid detoxification have been reported. 7 Of particular concern is the fact that the use of opioid antagonists results in loss of tolerance to opioids, rendering patients susceptible to overdose if they return to predetoxification dosage of illicit drugs. 8 Relapse after ultrarapid detoxification was examined in a 2014 study by Salimi et al. 9 A total of 424 patients with self-reported opioid use entered a treatment program at a single institution in Iran. Treatment consisted of rapid detoxification under general anesthesia and naltrexone maintenance therapy. Four hundred (94%) of the 424 patients completed 2 years of follow-up. Among completers, 97 (24%) patients experienced at least 1 incident of relapse. Patients who relapsed had significantly lower rates of long-term compliance with naltrexone therapy, and all of the patients who relapsed had discontinued naltrexone use prior to relapse. Mild AEs were Page 4

common and did not differentiate between patients with successful abstinence versus relapse. For example, 52% of those with treatment success and 56% who relapsed (p>0.05) experienced mild muscle pain in the first 3 months after withdrawal. This study was uncontrolled and does not provide data on the relative efficacy of detoxification methods. A follow-up study was done by Forozesshfard et al to evaluate relapse after Ultrarapid detoxification. 10 This was a prospective study done in Iran and included 64 patients undergoing the procedure with general anesthesia, followed by outpatient treatment using naltrexone oral therapy, and free-of-charge monthly psychiatric visits. Of the 64 patients undergoing treatment, 48 (75%) patients suffered relapse within the first month, with 12 patients returning to opioid abuse at 3 months, and the remaining 4 patients by 6 months. Four (6%) patients had lifethreatening complications during the procedure, including pulmonary edema, pneumothorax, bradycardia, and refractory delirium with hypertension and cardiac arrhythmia. None of these patients had a fatal event. Ongoing and Unpublished Clinical Trials A search of ClinicalTrials.gov in November 2015 did not identify any ongoing or unpublished trials that would likely influence this review. Summary of Evidence The evidence for ultrarapid detoxification under general anesthesia in individuals who have opioid addiction includes both randomized and nonrandomized clinical trials, as well as prospective follow-up studies, which compare other approaches not involving deep or general anesthesia. Relevant outcomes are change in disease status, treatment-related morbidity and mortality, in addition to continued abstinence from opioids or relapse to daily opioid use. There is a paucity of data in the controlled trials and a lack of standardized approach to ultrarapid detoxification. Additionally, significant adverse effects, including life-threatening complications, are a concern using this treatment. Most patients subsequently return to daily use shortly after this technique. The evidence is insufficient to determine the effects of the technology on health outcomes. Practice Guidelines and Position Statements National Institute for Health and Clinical Excellence In 2007, the National Institute for Health and Clinical Excellence issued clinical practice guidelines on drug misuse, opioid detoxification. The guidelines include the following statement regarding ultrarapid detoxification, Ultra-rapid detoxification under general anesthesia or heavy sedation (where the airway needs to be supported) must not be offered. This is because of the risk of serious adverse events, including death. American Psychiatric Association In 2007, the American Psychiatric Association Work Group on Substance Use Disorders released a practice guideline for the treatment of patients with substance use disorders. 12 The practice guideline included the following recommendation: Anesthesia-assisted rapid opioid Page 5

detoxification is not recommended because of lack of proven efficacy and adverse risk-benefit ratios. American Society of Addiction Medicine In 2005, the American Society of Addiction Medicine (ASAM) published a public policy statement regarding opiate detoxification under sedation or anesthesia. It included the following position statements: Opioid detoxification alone is not a treatment of opioid addiction. ASAM does not support the initiation of acute opioid detoxification interventions unless they are part of an integrated continuum of services that promote ongoing recovery from addiction. Ultra-Rapid Opioid Detoxification (UROD) is a procedure with uncertain risks and benefits, and its use in clinical settings is not supportable until a clearly positive risk-benefit relationship can be demonstrated. Further research on UROD should be conducted. Although there is medical literature describing various techniques of Rapid Opioid Detoxification (ROD), further research into the physiology and consequences of ROD should be supported so that patients may be directed to the most effective treatment methods and practices. U.S. Preventive Services Task Force Recommendations No U.S. Preventive Services Task Force recommendations for opioid detoxification under heavy sedation or general anesthesia have been identified. Medicare National Coverage Medicare policy on this issue is as follows. Section 130.7, of the Medicare Coverage Issues Manual (Medical Procedures), Withdrawal Treatment for Narcotic Addictions, states: Withdrawal is an accepted treatment for narcotic addiction, and Part B payment can be made for these services if they are provided by the physician directly or under his personal supervision and if they are reasonable and necessary. In reviewing claims, reasonableness and necessity are determined with the aid of the B/Medicare Administrative Contractor s medical staff. Drugs that the physician provides in connection with this treatment are also covered if they cannot be self-administered and meet all other statutory requirements. Cross-reference: Medicare Benefit Policy Manual, Chapter 6, Hospital Services Covered Under Part B, 20.4.1. Section 130.6, Treatment of Drug Abuse (Chemical Dependency), states: The Centers for Medicare & Medicaid Services recognizes that there are similarities between the approach to treatment of drug abuse and alcohol detoxification and rehabilitation. However, the intensity and duration of treatment for drug abuse may vary (depending on the particular substance(s) of abuse, duration of use, and the patient s medical and emotional condition) from Page 6

the duration of treatment or intensity needed to treat alcoholism. Accordingly, when it is medically necessary for a patient to receive detoxification and/or rehabilitation for drug substance abuse as a hospital inpatient, coverage for care in that setting is available. Coverage is also available for treatment services that are provided in the outpatient department of a hospital to patients who, for example, have been discharged from an inpatient stay for the treatment of drug substance abuse or who require treatment but do not require the availability and intensity of services found only in the inpatient hospital setting. The coverage available for these services is subject to the same rules generally applicable to the coverage of outpatient hospital services. (See the Medicare Benefit Policy Manual (BPM), Chapter 6, Hospital Services Covered Under Part B, 20.) The services must also be reasonable and necessary for treatment of the individual s condition. (See the Medicare BPM, Chapter 16, General Exclusions from Coverage, 90.) Decisions regarding reasonableness and necessity of treatment, the need for an inpatient hospital level of care and length of treatment, should be made by A/B Medicare Administrative Contractors (MACs) based on accepted medical practice with the advice of their medical consultant. (In hospitals under Quality Improvement Organization (QIO) review, QIO determinations of medical necessity of services and appropriateness of the level of care at which services are provided are binding on A/B MACs for purposes of adjudicating claims for payment.) V. DEFINITIONS TOP OPIOID refers to any synthetic narcotic not derived from opium VI. BENEFIT VARIATIONS TOP The existence of this medical policy does not mean that this service is a covered benefit under the member's contract. Benefit determinations should be based in all cases on the applicable contract language. Medical policies do not constitute a description of benefits. A member s individual or group customer benefits govern which services are covered, which are excluded, and which are subject to benefit limits and which require preauthorization. Members and providers should consult the member s benefit information or contact Capital for benefit information. VII. DISCLAIMER TOP Capital s medical policies are developed to assist in administering a member s benefits, do not constitute medical advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of members. Members should discuss any medical policy related to their coverage or condition with their provider Page 7

and consult their benefit information to determine if the service is covered. If there is a discrepancy between this medical policy and a member s benefit information, the benefit information will govern. Capital considers the information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law. VIII. CODING INFORMATION TOP Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement. *No specific CPT codes* IX. REFERENCES TOP 1. Gowing L, Ali R, White J. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev. 2010(1):CD002022. 2. Collins ED, Kleber HD, Whittington RA, et al. Anesthesia-assisted vs buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial. Jama. 2005;294(8):903-913. 3. Bearn J, Gossop M, Strang J. Rapid opiate detoxification treatments. Drug Alcohol Rev. 1999;18(1):75-81. 4. Dyer C. Addict died after rapid opiate detoxification. Bmj. 1998;316(7126):170. 5. Gold CG, Cullen DJ, Gonzales S, et al. Rapid opioid detoxification during general anesthesia: a review of 20 patients. Anesthesiology. 1999;91(6):1639-1647. 6. Solomont JH. Opiate detoxification under anesthesia. Jama. 1997;278(16):1318-1319. 7. Brewer C, Laban M, Schmulian C, et al. Rapid opiate detoxification and naltrexone induction under general anaesthesia and assisted ventilation: experience with 510 patients in four different centres Acta Psychiatr Belg 1998;98:181-189. 8. American Society of Addiction Medicine. Public Policy Statement on Opioid Antagonist Agent Detoxification Under Sedation Or Anesthesia (OADUSA). J Addict Dis. 2000;19(4):109-112. 9. Salimi A, Safari F, Mohajerani SA, et al. Long-term relapse of ultra-rapid opioid detoxification. J Addict Dis. 2014;33(1):33-40. PMID 24471478 10. Forozeshfard M, Hosseinzadeh Zoroufchi B, Saberi Zafarghandi MB, et al. Six-month follow-up study of ultrarapid opiate detoxification with naltrexone. Int J High Risk Behav Addict. Dec 2014;3(4):e20944. PMID 25741479 Page 8

11. National Institute for Health and Clinical Evidence. Drug misuse, opioid detoxification. NICE Clinical Guideline 52. http://www.nice.org.uk/guidance/cg52. Accessed February 15, 2016. 12. Kleber HD, Weiss RD, Anton RF, et al. Work Group on Substance Use Disorders. Treatment of patients with substance use disorders. American Psychiatric Association. Am J Psychiatry. 2006;163(8 suppl):5-82. 13. American Society of Addiction Medicine. Public Policy Statement on Rapid and Ultra Rapid Opioid Detoxification. http://www.asam.org/advocacy/find-a-policy-statement/view-policystatement/public-policy-statements/2011/12/15/rapid-and-ultra-rapid-opioid-detoxification. Accessed February 15, 2016. 14. Center for Medicaid and Medicare Services. Medicare Policy 130-7 https://www.cms.gov/regulations-and- Guidance/Guidance/Manuals/downloads/ncd103c1_part2.pdf. Accessed February 15, 2016. Other Sources: 1. Centers for Medicare and Medicaid Services (CMS) National Coverage Decision (NCD) 130.6, Treatment of Drug Abuse (Chemical Dependency). CMS [Website: http://www.cms.gov/medicare-coverage-database/details/ncddetails.aspx?ncdid=28&ncdver=1&docid=130.6+&bc=gaaaaagaaaaa& Accessed February 15, 2016. 2. Centers for Medicare and Medicaid Services (CMS) National Coverage Decision (NCD) 130.7, Withdrawal Treatments for Narcotic Addictions. CMS [Website]: http://www.cms.gov/medicare-coverage-database/details/ncddetails.aspx?ncdid=59&ncdver=1&docid=130.7&bc=gaaaaagaaaaa& Accessed February 15, 2016. X. POLICY HISTORY TOP MP 2.203 CAC 5/27/03 CAC 4/26/05 CAC 4/25/06 CAC 4/24/07 Consensus CAC 5/27/08 Consensus CAC 5/26/09 Consensus CAC 5/25/10 Consensus CAC 9/10 Adopted BCBSA Guidelines CAC 7/26/11 Consensus CAC 8/28/12 Consensus, no change to policy statements, references updated Codes reviewed 8/20 /12 CAC 07/30/13- Consensus review. Admin code review complete. Page 9

CAC 3-25-14 Consensus. No change to policy statements. References updated. Rationale section added. Coding complete. CAC 3/24/15 Consensus review. No change to the policy statement. Reference and rationale updated. Coding reviewed. CAC 3/29/16 Consensus review. No change to policy statement. References and rationale updated. Coding reviewed. Admin update 1/1/17: Product variation section reformatted. Top Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company, Capital Advantage Assurance Company and Keystone Health Plan Central. Independent licensees of the BlueCross BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies. Page 10